Neovascularization is a recognized but poorly understood component of neointimal formation in atherosclerotic lesions. We have demonstrated that the potent angiogenic factor vascular endothelial growth factor (VEGF) is expressed in vascular cells and is regulated by known modulators of atherogenesis. We hypothesize that VEGF is of central importance in the neovascularization process and that it contributes in this way to the progression of atherosclerotic lesions. Because of the association between atherosclerosis and aging and because factors that regulate VEGF expression are linked to the pathologies of aging, we anticipate that altered regulation of neovascularization through factors such as VEGF may contribute to the vasculopathy of aging. In order to explicate the role of VEGF in atherosclerosis-associated neovascularization, we propose in this small grant application to establish systems to address this question both in vivo and in vitro, using state of the art molecular and cellular biology techniques. We have previously demonstrated that VEGF is regulated by reactive oxygen species (ROS), and that VEGF is upregulated in vivo in a baboon brachial artery model of neointimal formation. We propose to examine the signaling, transcriptional, and/or posttranscriptional mechanisms by which ROS regulate VEGF in vascular smooth muscle cells (VSMC). We will then address the age-related mechanisms by which VEGF is regulated in vascular cells by examining VEGF regulation in passaged VSMC and in VSMC derived from aged animals. Lastly, animal models will be developed to fully characterize the role of VEGF and of neovascularization in neointimal formation in vivo. This small grant application is intended to provide initial data and specific models to address the role of VEGF in atherogenesis. Knowledge gained from this proposal should be an important first step in delineating essential mechanisms in atherosclerosis and in the vascular biology of aging. In addition, novel targets for intervention may be identified to prevent or halt the progression of atherosclerosis in these patient populations.